Genetic variations in genes involved in the metabolic activation and/or detoxification of tobacco carcinogens are likely to be a major source of inter-individual and inter-racial variation in cancer susceptibility. These metabolic differences are often associated with genetic polymorphisms in genes coding for carcinogen metabolizing enzymes. Therefore, the carcinogenic capacity of tobacco and tobacco smoke may be dependent upon the genetic composition of enzymes responsible for metabolizing of these carcinogens, thereby affecting individual susceptibility to tobacco- related cancers. One of the important enzymes involved in the metabolism of major tobacco-smoke carcinogens including | polycyclic aromatic hydrocarbons like benzo[a]pyrene (BaP) is epoxide hydrolase (EH). The EH enzyme catalyzes the conversion of BaP-(7,8)-epoxide to BaP-(7,8)-diol, which is the direct precursor metabolite of BaP-(7,8)-diol-(9,10)-epoxide, the ultimate carcinogen of BaP. Previous studies have implicated EH polymorphisms in increased risk for lung as well as oral cancer in Caucasian cohorts but have not included an | assessment of EH polymorphisms and cancer risk in other racial groups. We have established the presence of other EH gene polymorphisms that could potentially play a role in EH activity. As EH plays a key role in the activation of PAHs, a full exploration of EH genetic variants must be performed and the role of polymorphic EH alleles on EH activity. Our hypothesis is that newly-identified EH genetic polymorphisms play an important role in affecting enzyme activity. The goal of the present study is to elucidate novel and examine known or newly-identified polymorphisms present in the EH gene. In this proposal, we intend to examine the prevalence of newly identified as well as known polymorphisms in Caucasians as well as African Americans. In addition, we will examine the potential role of these polymorphisms in EH activity by functional analysis of each allele. These studies will provide baseline information for future large-scale case:control studies regarding the potential of these polymorphisms to affect cancer risk and influence our strategies in terms of cancer prevention for smoking-related cancers.